Adenosine is a naturally occurring nucleoside that exerts its biological effects by interacting with a family of adenosine receptors identified as the adenosine A1, A2a, A2b, and A3 receptors, all of which modulate important physiological processes. For example, stimulation of the adenosine A1 receptors shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of adenosine A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. Adenosine A2A receptors modulate coronary vasodilation, adenosine A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153).
A3 adenosine receptors modulate a variety of biological processes. In particular, compounds that are A3 adenosine receptor agonists have utility in the therapeutic and/or prophylactic treatment of cancer, cardiac disease, infertility, kidney disease, and CNS disorders. Additionally, A3 adenosine receptor agonists stimulate the secretion of G-CSF, a cytokine involved with the growth and differentiation of bone marrow cells. Accordingly, A3 adenosine receptor agonists are useful for countering the cytotoxic side effect of drugs, in particular chemotherapeutic drugs, such as leukopenia and neutropenia.
Few ligands for the A3 adenosine receptor have been reported. A non-selective N6-substituted adenosine derivatives, known as APNEA (N6-2-(4-aminophenyl)ethyladenosine, was reported by Zhou (Zhou et al. 1992. PNAS. 89(16):7432). Such compounds have been used experimentally but provide no therapeutic benefit. Also, 2-alkynyl-N6-substituted adenosines that are agonists at the A3 adenosine receptor have been produced. (Cristalli et al. 2000. Drug Dev. Res. 50(1):072.
Accordingly, it is desired to provide compounds that are A3 adenosine receptor agonists. Preferably, the compounds would be selective for the A3 adenosine receptor, thus avoiding side effects caused by interaction with other adenosine receptors.